Cholesterol Nanodomain Formation in Lipid Membranes

脂质膜中胆固醇纳米域的形成

• 批准号: 7010094
• 负责人: STEVEN P WRENN
• 金额: $ 20.21万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010094
• 关键词: atherosclerotic plaque; cell line; cell membrane; chemical aggregate; cholelithiasis; cholesterol; crystallization; human tissue; lipid structure; low density lipoprotein; macrophage; membrane lipids; vesicle /vacuole

DESCRIPTION (provided by applicant): This proposal aims to provide a fundamental understanding of cholesterol crystal nucleation from biliary vesicles and plasma lipoproteins in the context of gallstone disease and atherosclerosis, respectively. Cholesterol crystals are precursors to gallstones; inhibiting cholesterol nucleation offers a potential means of preventing stones. Crystals are also considered to be hallmarks of advanced atherosclerotic plaques, which typically become life-threatening only after rupture, followed by thrombosis and occlusion of an artery. Given that plaque stability correlates with the presence of crystals, inhibiting cholesterol nucleation offers a potential means of maintaining stability of atherosclerotic lesions and protecting against myocardial infarction. Development of preventive, clinical strategies based on inhibiting cholesterol nucleation requires a fundamental understanding of the nucleation mechanism. Molecular details concerning cholesterol nucleation are lacking, both in blood and in bile. However, recent work has shed important new insights, and kinetic and mechanistic studies of cholesterol nucleation are now feasible. This proposal is designed to test the hypotheses that 1) nanodomains of laterally phase-separated cholesterol constitute an equilibrium phase within lipid membranes; these nanondomains are distinct from cholesterol-rich domains and rafts 2) cholesterol nanodomains can act as crystal nucleation sites in non-equilibrium (i.e., in vivo) systems, and 3) aggregation of either vesicles or low density lipoproteins (LDL) facilitates collisions of cholesterol nanodomains in adjacent membranes; whereas aggregation alone is sufficient to induce nucleation from vesicles, nucleation from LDL requires uptake by macrophages.

描述（由申请人提供）： 该提案旨在分别在胆结石疾病和动脉粥样硬化的背景下，对胆汁囊泡和血浆脂蛋白的胆固醇晶体成核的基本了解。胆固醇晶体是胆结石的前体。抑制胆固醇成核提供了预防石头的潜在手段。晶体也被认为是晚期动脉粥样硬化斑块的标志，通常只有在破裂后才会威胁生命，然后进行血栓形成和动脉阻塞。鉴于斑块稳定性与晶体的存在相关，抑制胆固醇成核提供了维持动脉粥样硬化病变稳定性并预防心肌梗塞的潜在方法。 基于抑制胆固醇成核的预防性，临床策略的发展需要对成核机制有基本的了解。在血液和胆汁中都缺乏有关胆固醇成核的分子细节。然而，最近的工作已经提供了重要的新见解，现在可行的胆固醇成核的动力学和机械研究。 该建议旨在检验1）侧相分离胆固醇的纳米域在脂质膜内构成平衡相； these nanondomains are distinct from cholesterol-rich domains and rafts 2) cholesterol nanodomains can act as crystal nucleation sites in non-equilibrium (i.e., in vivo) systems, and 3) aggregation of either vesicles or low density lipoproteins (LDL) facilitates collisions of cholesterol nanodomains in adjacent membranes;尽管仅聚集足以诱导囊泡的成核，但LDL的成核需要巨噬细胞的吸收。